Chronic Running Exercise Alleviates Early Progression of Nephropathy with Upregulation of Nitric Oxide Synthases and Suppression of Glycation in Zucker Diabetic Rats

Abstract

Exercise training is known to exert multiple beneficial effects including renal protection in type 2 diabetes mellitus and obesity. However, the mechanisms regulating these actions remain unclear. The present study evaluated the effects of chronic running exercise on the early stage of diabetic nephropathy, focusing on nitric oxide synthase (NOS), oxidative stress and glycation in the kidneys of Zucker diabetic fatty (ZDF) rats. Male ZDF rats (6 weeks old) underwent forced treadmill exercise for 8 weeks (Ex-ZDF). Sedentary ZDF (Sed-ZDF) and Zucker lean (Sed-ZL) rats served as controls. Exercise attenuated hyperglycemia (plasma glucose; 242 ± 43 mg/dL in Sed-ZDF and 115 ± 5 mg/dL in Ex-ZDF) with increased insulin secretion (plasma insulin; 2.3 ± 0.7 and 5.3 ± 0.9 ng/mL), reduced albumin excretion (urine albumin; 492 ± 70 and 176 ± 11 mg/g creatinine) and normalized creatinine clearance (9.7 ± 1.4 and 4.5 ± 0.8 mL/min per body weight) in ZDF rats. Endothelial (e) and neuronal (n) NOS expression in kidneys of Sed-ZDF rats were lower compared with Sed-ZL rats (p<0.01), while both eNOS and nNOS expression were upregulated by exercise (p<0.01). Furthermore, exercise decreased NADPH oxidase activity, p47phox expression (p<0.01) and α-oxoaldehydes (the precursors for advanced glycation end products) (p<0.01) in the kidneys of ZDF rats. Additionally, morphometric evidence indicated renal damage was reduced in response to exercise. These data suggest that upregulation of NOS expression, suppression of NADPH oxidase and α-oxoaldehydes in the kidneys may, at least in part, contribute to the renal protective effects of exercise in the early progression of diabetic nephropathy in ZDF rats. Moreover, this study supports the theory that chronic aerobic exercise could be recommended as an effective non-pharmacological therapy for renoprotection in the early stages of type 2 diabetes mellitus and obesity.

Nebivolol ameliorated kidney damage in Zucker diabetic fatty rats by regulation of oxidative stress/NO pathway: Comparison with captopril

“…In contrast, NO exhibits various renoprotective effects that counteract the effects of OS. Evidence indicates that impaired NO contributes to the development of DN . In fact, endothelial nitric oxide synthase (eNOS) knockout mice developed DM with progressive nephropathy .…”

Physical activity protects NLRP3 inflammasome-associated coronary vascular dysfunction in obese mice

“…For example, Ito et al. () found that running exercise improved a reduced formation of nitrate/nitrite metabolites in renal cortex and outer medullar of diabetic Zucker rats. Silva et al.…”

“…These results support previous reports in the literature. For example, Ito et al (2015) found that running exercise improved a reduced formation of nitrate/nitrite metabolites in renal cortex and outer medullar of diabetic Zucker rats. Silva et al (2016) reported that treadmill exercise training reversed downregulation of eNOS protein expression in the aorta of high-sugary diet-induced obese mice.…”

Intra-Renal Hemodynamic Changes After Habitual Physical Activity in Patients with Chronic Kidney Disease

“…An animal study by Ito et al [42], who examined the chronic effects of running in Zucker diabetic fatty rats showed that at early stages of diabetic nephropathy, running beneficially induce alterations in kidney oxidative stress status. More precisely, the 8 weeks running on a treadmill increased NOS activity and protein expression of eNOS and nNOS proteins in the renal cortex of the diabetic rats, suggesting that exercise training may provide renoprotective effects and delay the progression of renal failure at the early stages of diabetic nephropathy [42]. In addition, the renoprotective effects of exercise training have been proved in a study by Tucker et al [43], where the authors compare the effects of high intensity interval training with light intensity exercise training or with a sedentary group of rats.…”